Research in Nianli Sang’s lab has been focusing on a better understanding of cells’ response to insufficiency of oxygen, glucose and glutamine supplies, a condition commonly occurring in solid tumors and ischemic lesions. Due to defective blood vessels, tumor microenvironment is characterized by lack of molecular oxygen, glucose and glutamine. In addition, a variety of cardiovascular disorders such as coronary artery insufficiency and stroke lead to tissue ischemia. Our working model is that tumor cells and normal cells alike have sensing mechanisms that monitor the supply status of these basic nutrients; and in response to nutrient insufficiency, the sensing mechanisms will trigger transcriptional and metabolic reprogramming, which eventually facilitates cell survival or leads to migration. These adaptive responses may contribute to cancer invasion and metastasis, but may be critical for normal cells to survive temporary ischemia. Sang’s lab has taken the genome-wide, unbiased mRNA profiling approach (microarray), to screen genes that are upregulated or down-regulated by lack of oxygen, glucose or glutamine. These screening will generate the dataset which can be used to dissect the global gene expression reprogramming, regulatory network, and signaling pathways. Following these screening and bioinformatics analyses, specific genes and pathways can be chosen for further investigation.
Specifically, one line of Sang’s research focuses on hypoxia-inducible factor 1, the major transcription factor mediates cells response to hypoxia. Nianli Sang’s group has revealed a ubiquitination-independent degradation pathway of HIF-1α, which is related to the disposal of misfolded HIF-1α caused by stresses associated with nutrient insufficiency and chemotherapy. Sang also has started to dissect the signaling pathways, transcriptional and metabolic reprogramming triggered by insufficient supply of glucose and glutamine. This line of research has revealed that the activation of ER stress pathway, which involves Grp78, ATF4 and STC2, is critical for cells to survival under stress conditions. Towards that direction, Nianli Sang’s group is going to address: 1) what are the cellular level sensing systems for glucose and glutamine? 2) How do oncogenic signaling pathways stimulate and coordinate the utilization of glucose and glutamine? 3) how will lack of glucose and glutamine together with hypoxia contributes to tumor migration and metastasis? and 4) does the ER stress responsive pathway play critical roles in tumor resistance to chemo-radiotherapy?
Prior Research Funding:
Total Award: $1,563,600
“Repressing HIF-1: targets and mechanisms”